Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.
PSD-95 is a major scaffolding protein of the postsynaptic density, tethering NMDA- and AMPA-type glutamate receptors to signaling proteins and the neuronal cytoskeleton. Here we show that PSD-95 is regulated by the ubiquitin-proteasome pathway. PSD-95 interacts with and is ubiquitinated by the E3 ligase Mdm2. In response to NMDA receptor ... activation, PSD-95 is ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that block PSD-95 ubiquitination prevent NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevent NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. This is consistent with the notion that PSD-95 levels are an important determinant of AMPA receptor number at the synapse. These data suggest that ubiquitination of PSD-95 through an Mdm2-mediated pathway is critical in regulating AMPA receptor surface expression during synaptic plasticity.
Mesh Terms:
Acetylcysteine, Analysis of Variance, Animals, Animals, Newborn, Blotting, Western, Calcium, Cells, Cultured, Cysteine Proteinase Inhibitors, Drug Interactions, Electric Stimulation, Embryo, Mammalian, Endocytosis, Epitopes, Excitatory Amino Acid Agonists, Forskolin, Hippocampus, Humans, Immunoglobulin G, Immunohistochemistry, Immunosuppressive Agents, Intracellular Signaling Peptides and Proteins, Kidney, Leupeptins, Membrane Potentials, Membrane Proteins, Mutation, N-Methylaspartate, Nerve Tissue Proteins, Neural Inhibition, Neurons, Nuclear Proteins, Patch-Clamp Techniques, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Rats, Rats, Long-Evans, Receptors, AMPA, Synapses, Synapsins, Tacrolimus, Time Factors, Transfection, Ubiquitin
Acetylcysteine, Analysis of Variance, Animals, Animals, Newborn, Blotting, Western, Calcium, Cells, Cultured, Cysteine Proteinase Inhibitors, Drug Interactions, Electric Stimulation, Embryo, Mammalian, Endocytosis, Epitopes, Excitatory Amino Acid Agonists, Forskolin, Hippocampus, Humans, Immunoglobulin G, Immunohistochemistry, Immunosuppressive Agents, Intracellular Signaling Peptides and Proteins, Kidney, Leupeptins, Membrane Potentials, Membrane Proteins, Mutation, N-Methylaspartate, Nerve Tissue Proteins, Neural Inhibition, Neurons, Nuclear Proteins, Patch-Clamp Techniques, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Rats, Rats, Long-Evans, Receptors, AMPA, Synapses, Synapsins, Tacrolimus, Time Factors, Transfection, Ubiquitin
Neuron
Date: Oct. 30, 2003
PubMed ID: 14642282
View in: Pubmed Google Scholar
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